A team of researchers at the University of California, Los Angeles (UCLA) has identified an optimal design for a new type of immunotherapy that could be mass-produced to treat various solid tumors. The study focused on engineered invariant natural killer T cells (NKT cells), which have the ability to penetrate solid tumors, and compared four different chimeric antigen receptors (CARs) that guide these immune cells to attack cancer.
While CAR-T cell therapies have been effective in treating certain blood cancers such as leukemia and lymphoma, they have not shown similar success against solid tumors. Solid tumors often form protective barriers that prevent therapeutic cells from reaching them and display diverse targets, making it difficult for immune therapies to detect all cancerous cells.
The UCLA research team highlighted advantages of CAR-NKT cells over traditional CAR-T approaches. These engineered NKT cells can find tumors more efficiently and break through tissue barriers that hinder other treatments. They also kill both cancer cells and the immunosuppressive cells that protect tumors.
To determine which CAR design is most effective, the researchers engineered human blood stem cells to produce NKT cells equipped with four types of CARs. Each targeted mesothelin—a protein found on ovarian, pancreatic, lung, and breast cancers—using different molecular “engines”: CD28, 4-1BB, a combination of CD28/4-1BB, or NKG2D/2B4.
In laboratory tests against tumor samples from several cancers and in mouse models of ovarian cancer, the version containing 4-1BB showed the strongest anti-tumor activity and persistence over time.
According to senior author Lili Yang, professor at UCLA’s Department of Microbiology, Immunology and Molecular Genetics: “By rigorously identifying the optimal CAR design for NKT cells, our findings provide a roadmap for advancing CAR-NKT cell therapies from the lab toward clinical trials.”
Researchers reported no observed safety concerns; the modified NKT cells did not harm healthy tissues or cause graft-versus-host disease—a risk when using donor-derived immune therapies—and did not grow uncontrollably.
One significant aspect noted by the research team is the therapy’s off-the-shelf potential. Unlike current CAR-T treatments—which require collecting each patient’s immune cells before modification—CAR-NKT cell therapy can be produced from donated blood stem cells in advance and stored at hospitals for immediate use when needed.
The study was published in Blood Immunology & Cellular Therapy. Authors include Yanruide Li, Yichen Zhu, Tyler Halladay, Xinyuan Shen, Youcheng Yang , Zhe Li, Enbo Zhu, Yuning Chen, Jie Huang and Lili Yang.
Funding came from sources including the California Institute for Regenerative Medicine; U.S. Department of Defense; UCLA Broad Stem Cell Research Center; Wendy Ablon Trust; Parker Institute for Cancer Immunotherapy; UCLA departments; Office of the Chancellor; and Goodman-Luskin Microbiome Center.
